Current state and outlook for drug repositioning anticipated in the field of ovarian cancer

Kobayashi, Yusuke; Banno, Kouji; Kunitomi, Haruko; Tominaga, Eiichiro; Aoki, Daisuke

doi:10.3802/jgo.2019.30.e10

Cited by 31 publications

(26 citation statements)

References 71 publications

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“…33 YAP1, a downstream target of the Hippo pathway that regulates organ size during growth, is a multi-functional protein that can activate gene expression by interacting with different transcription factors. 34,35 Moreover, a large number of studies have associated increased accumulation of YAP1 in the nucleus with poor prognosis in patients with intrahepatic cholangiocellular carcinoma (ICC) and combined hepatocellular and cholangiocarcinoma (cHC-CC), 33 colorectal cancer (CRC), 36 ovarian cancer 35,37,38 and gastric cancer (GC). 34 Through in vitro proliferation assays and a xenograft model, Nambara S found that ivermectin exerts its antitumour effects and inhibits the proliferation of GC by decreasing the expression of the YAP1 protein in the nucleus and suggested that the nuclear expression of YAP1 is slightly associated with the YAP1 mRNA levels.…”

Section: Ivermectin Modulates Several Pathwaysmentioning

confidence: 99%

<p>Progress in Understanding the Molecular Mechanisms Underlying the Antitumour Effects of Ivermectin</p>

Liu

Zhang

Cheng

et al. 2020

DDDT

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Ivermectin, a dihydro derivative of avermectin (AVM), was introduced into the veterinary, agricultural and aquaculture markets for animal health in 1981. Ivermectin was soon adopted in 1987 as a human medicine that was originally used for the treatment of onchocerciasis, a parasitic infection. Since then, ivermectin has also been used to control other human diseases and has exerted a significant effect on human health and welfare. In the past decade, many published studies have attempted to determine the role of ivermectin in cancer. In this review, we summarize the published studies to define the current progress in the characterization of ivermectin. Ivermectin causes cell death in cancer cell lines by inducing PAK1-mediated cytostatic autophagy, caspase-dependent apoptosis and immunogenic cell death (ICD) through the modulation of some pathways, including the WNT-T cell factor (TCF), Hippo and Akt/ mTOR pathways. Ivermectin can affect the growth and proliferation of cancer cells and plays several different roles, such as its functions as an RNA helicase, a small-molecule mimetic of the surface-induced dissociation (SID) peptide, an activator of chloride channel receptors, and an inducer of mitochondrial dysfunction and oxidative stress. In addition, ivermectin induces the multidrug resistance protein (MDR), has potent anti-mitotic activity, targets angiogenesis and inhibits cancer stem-like cells (CSCs). Many studies have proven that ivermectin exerts antitumour effects and might thus benefit patients with cancer after sufficient clinical trials.

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Section: Ivermectin Modulates Several Pathwaysmentioning

confidence: 99%

<p>Progress in Understanding the Molecular Mechanisms Underlying the Antitumour Effects of Ivermectin</p>

Liu

Zhang

Cheng

et al. 2020

DDDT

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“…Overall, these observations have prompted suggestions of clinical trials incorporating statin drugs with current treatment regimens [13]. Such actions are particularly timely, since it is being increasingly recognized that the 10-15 year development cycle and billion-plus dollar investment required to bring novel drugs to market is probably unsustainable in the framework of current national and global healthcare [35]. Consequently, the concepts of "drug repurposing" and "drug repositioning" have been advanced [36].…”

Section: Discussionmentioning

confidence: 99%

Statin Drugs Plus Th1 Cytokines Potentiate Apoptosis and Ras Delocalization in Human Breast Cancer Lines and Combine with Dendritic Cell-Based Immunotherapy to Suppress Tumor Growth in a Mouse Model of HER-2pos Disease

et al. 2020

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A dendritic cell-based, Type 1 Helper T cell (Th1)-polarizing anti-Human Epidermal Growth Factor Receptor-2 (HER-2) vaccine supplied in the neoadjuvant setting eliminates disease in up to 30% of recipients with HER-2-positive (HER-2pos) ductal carcinoma in situ (DCIS). We hypothesized that drugs with low toxicity profiles that target signaling pathways critical for oncogenesis may work in conjunction with vaccine-induced immune effector mechanisms to improve efficacy while minimizing side effects. In this study, a panel of four phenotypically diverse human breast cancer lines were exposed in vitro to the combination of Th1 cytokines Interferon-gamma (IFN-γ) and Tumor Necrosis Factor-alpha (TNF-α) and lipophilic statins. This combination was shown to potentiate multiple markers of apoptotic cell death. The combination of statin drugs and Th1 cytokines minimized membrane K-Ras localization while maximizing levels in the cytoplasm, suggesting a possible means by which cytokines and statin drugs might cooperate to maximize cell death. A combined therapy was also tested in vivo through an orthotopic murine model using the neu-transgenic TUBO mammary carcinoma line. We showed that the combination of HER-2 peptide-pulsed dendritic cell (DC)-based immunotherapy and simvastatin, but not single agents, significantly suppressed tumor growth. Consistent with a Th1 cytokine-dependent mechanism, parenterally administered recombinant IFN-γ could substitute for DC-based immunotherapy, likewise inhibiting tumor growth when combined with simvastatin. These studies show that statin drugs can amplify a DC-induced effector mechanism to improve anti-tumor activity.

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“…The results indicated that statin administration avoids the Warburg effect, which is unique to cancer cells, and activates the TCA cycle, shifting the energy production in cancer cells to oxidative phosphorylation. Since statins reduced the development of serous tubal intraepithelial carcinomas in transgenic ovarian cancer model mice and inhibited ovarian tumor growth in the mouse xenograft model, interfering Warburg effect may play an import role in statins anti‐tumor effect . Repositioning statin drugs for ovarian cancer may provide a promising strategy to prevent and manage this devastating disease.…”

Section: Gynecologic Cancers and The Warburg Effectmentioning

confidence: 99%

Warburg effect in Gynecologic cancers

Kobayashi

Banno

Kunitomi

et al. 2018

J of Obstet and Gynaecol

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Mammalian cells produce energy by oxidative phosphorylation under aerobic conditions. However, in the 1920s, Otto Warburg reported the so-called "Warburg effect" in which cancer cells produce ATP that is biased toward glycolysis rather than mitochondrial oxidative phosphorylation not only in anaerobic environment but also in aerobic environment. Glucose is converted into lactate without going into mitochondria after being metabolized in glycolysis. Compared with oxidative phosphorylation, the glycolysis has a faster ATP production rate but it is very inefficient, resulting in cancer cells consuming a large amount of glucose. Increased glucose metabolism has become a biomarker for cancer cells and has led to the development of positron emission tomography with fluorodeoxyglucose. Till date, the Warburg effect has been an inefficient system for cancer cells with regard to efficient energy production, but since the consumption of oxygen can be suppressed as the tumor grows in mass, it is thought that the Warburg effect is advantageous in this situation wherein the tumor can increase despite the lack of vessels. In addition, an increased lactate by the glycolysis causes acidosis in the microenvironment of tissues, which is thought to damage the surrounding normal tissues and favor the invasion and metastasis of cancer. Thus, Warburg effect is one of the key mechanisms for cancer development and will be the next promising target. In this review, we introduce key players that can be targeted in the Warburg effect and outline the prospects of treatment, targeting the Warburg effect in gynecological cancer.

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Current state and outlook for drug repositioning anticipated in the field of ovarian cancer

Cited by 31 publications

References 71 publications

<p>Progress in Understanding the Molecular Mechanisms Underlying the Antitumour Effects of Ivermectin</p>

<p>Progress in Understanding the Molecular Mechanisms Underlying the Antitumour Effects of Ivermectin</p>

Statin Drugs Plus Th1 Cytokines Potentiate Apoptosis and Ras Delocalization in Human Breast Cancer Lines and Combine with Dendritic Cell-Based Immunotherapy to Suppress Tumor Growth in a Mouse Model of HER-2pos Disease

Warburg effect in Gynecologic cancers

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